WO2012084214A1 - Bone substitute material - Google Patents
Bone substitute material Download PDFInfo
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- WO2012084214A1 WO2012084214A1 PCT/EP2011/006457 EP2011006457W WO2012084214A1 WO 2012084214 A1 WO2012084214 A1 WO 2012084214A1 EP 2011006457 W EP2011006457 W EP 2011006457W WO 2012084214 A1 WO2012084214 A1 WO 2012084214A1
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- WIPO (PCT)
- Prior art keywords
- hap
- cap
- bone
- substitute material
- porous
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
- A61L27/425—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of phosphorus containing material, e.g. apatite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Definitions
- the invention relates to a new biphasic bone substitute material with a bilayer structure based on calcium phosphate hydroxyapatite (CAP/HAP) which is impregnated with collagen fibers, a process for preparing that biphasic bone substitute material and the use thereof as implant or prosthesis to support bone formation, bone regeneration, bone repair, bone remodeling and/or bone
- CAP/HAP calcium phosphate hydroxyapatite
- a well known natural, osteoconductive bone substitute material that promotes bone growth in periodontal and maxillofacial osseous defects is Geistlich Bio-Oss®, commercially available from Geistlich Pharma AG. That material is manufactured from natural bone by a process described in US Patent No. 5,167,961, which enables preservation of the trabecular architecture and nanocrystalline structure of the natural bone, resulting in an excellent osteoconductive matrix which is not or very slowly resorbed.
- Tricalcium phosphate / hydroxyapatite (TCP/HAP) systems and their use as bone substitute materials are described, for example, in US-6,338,752 disclosing a process for preparing a biphasic cement of -TCP/HAP by heating a powder mixture of ammonium phosphate and HAP at 1200-1500 Q C.
- European Patent EP-285826 describes a process for the production of a layer of HAP on metallic and non-metallic bodies for implants by application of a layer of a- TCP and completely converting the -TCP layer into HAP by reaction with water of pH 2 to 7 at 80-100 e C.
- the product obtained is a metallic or non metallic body covered with a layer of HAP.
- WO 97/41273 describes a process for coating a substrate such as notably hydroxyapatite (HAP) or other calcium phosphates (CAP) with a coating of carbonated hydroxyapatite, i.e. hydroxyapatite wherein phosphate and/or hydroxyl ions are partially replaced by bicarbonate ions, by a process comprising (a) immersing the substrate in a solution of pH 6.8 to 8.0 containing calcium ions, phosphate ions and bicarbonate ions at a temperature lower than 50 °C, (b) heating the portion of the solution in contact with the substrate to a temperature of 50 to 80 °C until having a pH greater than 8, (c) maintaining the substrate in contact with the alkali solution obtained in step (b) to form a carbonated hydroxyapatite coating, and (d) taking the substrate off the solution and subjecting the coating to drying.
- HAP hydroxyapatite
- CAP calcium phosphates
- bicarbonate ions are disclosed to act as inhibitors of hydroxyapatite crystal growth, resulting in non-stoichiometric crystals containing defects and having rather small dimensions, namely 10-40 nm in length and 3-10 nm in width (see page 7, lines 1-7).
- the components of calcium phosphate / hydroxyapatite (CAP/HAP) systems, especially TCP/HAP systems differ in their thermodynamic stability. Due to this difference, when CAP/HAP systems are implanted into a mammal, in particular a human patient, the solubility of TCP and other calcium phosphates is higher in the body fluid than the solubility of HAP.
- the difference in solubility between calcium phosphates and HAP causes a breakdown of the unordered sinter structure of the CAP/HAP system because the better soluble compound CAP (e.g. TCP) is removed quicker than HAP.
- the sintered interconnection between CAP and HAP produced at high temperatures will also make a remarkable contribution to higher solubility of the device in the physiological environment.
- osteoclast activity and therefore to an accelerated ill-controlled resorption of the ceramic material and a risk of adverse inflammation reactions, especially when using a large amount of synthetic bone substitute material.
- PCT/EP2010/003590 was to provide a calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material which, like bone substitute material Gottlich Bio-Oss®, after being set in vivo enables the concentration of calcium ions on the surface of the material and within the local environment thereof to remain almost constant and thus does not lead to an increased osteoclast activity.
- CAP/HAP calcium phosphate/hydroxyapatite
- the new biphasic nanocrystalline CAP/HAP bone substitute material shows very interesting in vivo properties.
- the invention of international patent application No. PCT/EP2010/003590 thus relates to a biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material comprising a sintered CAP core and at least one uniform and closed epitactically grown layer of nanocrystalline HAP deposited on top of the sintered CAP core, whereby the epitactically grown nanocrystals have the same size and morphology as human bone mineral, i.e. a length of 30 to 46 nm and a width of 14 to 22 nm.
- CAP/HAP biphasic calcium phosphate/hydroxyapatite
- the sintered CAP core may comprise tricalcium phosphate (TCP), notably a- TCP ( -Ca 3 (PO4)2) or ⁇ -TCP (p-Ca 3 (P04) 2 ), and/or tetracalcium phosphate (TTCP)
- TCP tricalcium phosphate
- PO4 -Ca 3
- P04 p-Ca 3
- TTCP tetracalcium phosphate
- the sintered CAP core essentially consists of TCP, -TCP being preferred.
- the epitactically grown layer of nanocrystalline HAP is structurally and chemically nearly identical to the natural human bone mineral.
- the epitactically grown layer of nanocrystalline HAP generally has a thickness of at least from 15 to 50 nm, preferably at least from 20 to 40 nm, more preferably at least from 25 to 35 nm. That minimum thickness corresponds to one layer of HAP nanocrystals in epitaxial orientation.
- the epitactically grown layer of nanocrystalline HAP may comprise a single or multiple layers of HAP nanocrystals in epitaxial orientation.
- the thickness of the epitactically grown layer of nanocrystalline HAP which is related to the number of such layers of HAP nanocrystals in epitaxial orientation, will be selected according to the intended application of the bone substitute material as implant or prosthesis in differently loaded parts of the body.
- the bone substitute material of the invention is indeed designed to function in vivo as a living-like system progressively
- the sintered CAP core into hydroxyapatite similar in size and morphology to human bone mineral, the rate of that transformation being dependent on the rate of calcium release by the sintered CAP core, which is to a large extent controlled by the thickness of the epitactically grown layer of nanocrystalline HAP.
- the properties of the CAP/HAP bone substitute material are to a large extent controlled by the thickness of the epitactically grown layer of crystalline HAP.
- the term "properties" includes the ability of the CAP/HAP bone substitute to release a constant concentration of calcium ions to the local environment in vitro and in vivo.
- the thickness of the epitactically grown layer of nanocrystalline HAP is related to the ratio of the sintered CAP core material to HAP, said ratio being generally between 5:95 and 95:5, preferably from 10:90 to 90:10.
- the CAP/HAP bone substitute material may be a particulate or a granulate, the particles or granules having a desired size and shape.
- the particles or granules are approximately spherical and have a diameter of 1 to 5000 ⁇ ⁇ , preferably 10 to 5000 in particular 250 to 5000
- the CAP/HAP bone substitute material may also be a shaped body, e.g. a screw, a nail, a pin or a structure having the profile of an osseous body part such as notably a hip, a clavicle, a rib, a mandible or a skull part.
- a screw, a nail or a pin may be used in reconstructive orthopedic surgery for fixing a ligament to a bone, for example in the knee or the elbow.
- Such a structure having the profile of an osseous body part may be used in orthopedic surgery as prosthesis for replacing a missing or defective bone or bone part.
- the invention of international application No.PCT/EP2010/003590 further relates to a process of preparing the above defined CAP/HAP bone substitute material comprising the steps of
- nanocrystalline layer of HAP is present but before the transformation process is finished completely
- step d) optionally sterilizing the separated material coming from step c).
- the sintered CAP core material may comprise tricalcium phosphate (TCP), notably a-TCP ( -Ca3(P0 )2) or ⁇ -TCP ( -Ca3(PO4)2), and/or tetracalcium phosphate
- TCP tricalcium phosphate
- a-TCP -Ca3(P0 )2
- ⁇ -TCP -Ca3(PO4)2
- the sintered CAP core material essentially consists of TCP, a-TCP being preferred.
- the preparation of the sintered CAP core material may be performed by methods known in the art comprising first mixing powders of calcium hydrogen phosphate (CaHPOO, calcium carbonate and/or calcium hydroxide, then calcining and sintering the mixture within an appropriate temperature range, thereby giving a bulk sintered CAP core material (see e.g. Mathew M. et al., 1977, Acta. Cryst. B33: 1325; Dickens B. et al., 1974, J. Solid State Chemistry 10, 232; and Durucan C. et al., 2002, J. Mat. Sci., 37:963).
- CaHPOO calcium hydrogen phosphate
- CaHPOO calcium carbonate
- calcium hydroxide calcium hydroxide
- a bulk sintered TCP core material may thus be obtained by mixing powders of calcium hydrogen phosphate (CaHPO-t), calcium carbonate and/or calcium
- a bulk sintered TTCP core material may also be obtained by the above described process.
- the bulk sintered CAP material prepared by such methods may be porous with a porosity of 2 to 80 vol% and a wide distribution of pores.
- the porosity parameters will be selected according to the intended application of the CAP/HAP bone substitute material.
- the sintered CAP core material used in step b) may be
- a preform of sintered CAP core material having a desired shape and size, e.g. a screw, a nail, a pin or a structure having the profile of an osseous body part.
- Such a preform of any desired shape and size may be obtained from the bulk sintered core material prepared as described above, by using well known
- the aqueous solution of step b) may be pure water, a simulated body fluid or a buffer. Important is that the pH value of the immersing solution of step b) is nearly neutral and remains stable throughout the transformation process, preferably within a pH range from 5.5 to 9.0.
- the buffer may be any buffer in the above pH range but is preferably a phosphate buffer with or without calcium, magnesium and/or sodium.
- simulated body fluid refers to any solution that mimics a body fluid.
- the simulated body fluid has an ion concentration similar to that of blood plasma.
- the temperature range in step b) is generally between 10°C and 50°C, preferably between 25 and 45 °C, more preferably between 35°C and 40°C.
- the immersing step b) induces in a first phase a first-order phase transition of the CAP core material and therefore the nucleation of HAP nanocrystal precursors.
- the resulting HAP precursors from the first phase will grow and establish a closed (i.e. completely coating) epitactic nanocrystalline composite layer.
- the first HAP nanocrystal layer must be uniform and closed and epitaxially connected to the sintered CAP core material throughout its external surface, including, in the case of the sintered CAP core material being porous, in the pores thereof.
- the first-order phase transition may proceed within the newly formed bilayer composite to further transform the sintered CAP core material (TCP or TTCP) into nanocrystalline HAP.
- the sintered CAP core material TCP or TTCP
- calcium ions will be released for a controllable time by a slow diffusion controlled process until a part of the sintered CAP core material has been transformed into nanocrystalline HAP.
- the transformation time and therefore the rate of calcium release can be controlled by variation of the thickness of the HAP layer.
- the epitactically grown nanocrystalline HAP layer of appropriate thickness will be prepared in-vitro, the transformation of CAP into HAP being stopped before it is completed.
- transformation process of CAP into HAP will be reactivated by contact with the body fluids and the bone substitute material will function as a living-like system forming new hydroxyapatite similar in size and morphology to humane bone mineral.
- Step c) is therefore a very critical step.
- the exposure time in the aqueous solution of step b) is based upon the thickness of the HAP layer desired. At least one layer of nanocrystalline HAP in epitaxial orientation is necessary. It is essential that the transformation of CAP into HAP is not finished.
- the proper exposure time according to the thickness desired can be calculated by using several thermodynamic differential equations well known to the skilled person in the art of calcium phosphates and cement and concrete chemistry.
- Separating the solid material from the aqueous solution is usually performed by filtration and drying, using techniques well known in the art.
- the optional sterilizing step d) may be performed by techniques well known in the art such as gamma-irradiation.
- the epitactically grown HAP nanocrystals surrounding the sintered CAP core material are identical in size and morphology to the apatite crystals of natural human bone mineral as shown in Table 1 below.
- the CAP/HAP bone substitute material of the invention successfully mimics the composite or microstructure of bone and is representing a biomimetic material of human bone mineral.
- Crystal size * [nm] Crystal size" " [nm] a (1,0,0) 18 ( ⁇ 4) 15-21 b (0,1,0) 18 ( ⁇ 4) 15-21 c (0,0,1) 38 ( ⁇ 8) 34-45 * Crystal size analysis has been performed by using TEM (transmission electron microscopy), SPM (scanning probe microscopy techniques) as well as refinement of X-ray diffraction data by using the Bragg method.
- the constant concentration of calcium ions results in an improved adhesion of osteoblasts and osteoclasts to the HAP surface in the correct ratio for the osteogenesis and thus to a steady state in the cycle of bone regeneration.
- a surface is provided to which osteoblasts and osteoclasts readily attach in the correct ratio for bone regeneration.
- CAP/HAP bone substitute material can function as a matrix for bioactive molecules such as extracellular matrix proteins such as notably growth factors for bone regeneration. It has now been found that the adhesion of osteoblasts and osteoclasts to the
- HAP surface in the correct ratio for the osteogenesis can be further improved by impregnating the above defined porous CAP/HAP bone substitute material with collagen fibers such as to further mimic the in vivo natural processes of bone formation, bone regeneration, bone repair, bone remodeling and bone replacement by creating an environment closer to that of bone or damaged bone, namely a hydroxyapatite part and an organic matrix comprising collagen fibers.
- the collagen fibers are generally fibers of collagen type I, collagen type III or a mixture thereof, or fibers of collagen type II.
- phosphate/hydroxyapatite (CAP/HAP) bone substitute material comprising a sintered CAP core and at least one uniform and closed epitactically grown layer of nanocrystalline HAP deposited on top of the sintered CAP core, whereby the epitactically grown nanocrystals have the same size and morphology as human bone mineral, i.e. a length of 30 to 46 nm and a width of 14 to 22 nm, which is impregnated with collagen fibers at a weight ratio of said collagen fibers to said porous biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material of at least 2%.
- CAP/HAP porous biphasic calcium phosphate/hydroxyapatite
- nanocrystalline HAP including inside the pores, as shown by scanning electron microscopy.
- the weight ratio of said collagen fibers to said porous biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material is preferably at least 5%, in particular at least 8%. That weight ratio is generally from 2 to 80 %, preferably from 5 to 50 %, in particular from 8 to 25 %.
- the collagen fibers are fibers of collagen type I, collagen type III or a mixture thereof.
- the epitactically grown layer of nanocrystalline HAP generally has a thickness of at least from 15 to 50 nm, preferably at least from 20 to 40 nm, more preferably at least from 25 to 35 nm. That minimum thickness corresponds to one layer of HAP nanocrystals in epitaxial orientation.
- the thickness of the epitactically grown layer of nanocrystalline HAP is related to the ratio of the sintered CAP core material to HAP, said ratio being generally between 5:95 and 95:5, preferably from 10:90 to 90:10.
- the sintered CAP core material essentially consists of TCP, -TCP being preferred.
- the present invention further relates to a process of preparing the above porous biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material comprising the steps of
- phosphate/hydroxyapatite (CAP/HAP) bone substitute material comprising a sintered CAP core and at least one uniform and closed epitactically grown layer of nanocrystalline HAP deposited on top of the sintered CAP core, whereby the epitactically grown nanocrystals have the same size and morphology as human bone mineral, i.e. a length of 30 to 46 nm and a width of 14 to 22 nm, and
- the porous biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material may be a shaped body of porous CAP/HAP bone substitute material or a particulate or granulate of porous CAP/HAP.
- the porous (CAP/HAP) bone substitute material is a particulate or a granulate of porous CAP/HAP bone substitute material, the impregnated collagen fibers then also acting as a binder between the particles or granules, thus providing a porous collagen matrix surrounding and impregnating particles or granules of porous CAP/HAP bone substitute material. Pieces cut from that matrix show some elastic properties which are of advantage for their use as implants.
- step (a) is generally a vigorous mixing, the latter being conveniently performed in the case of the above preferred embodiment in a mixer having a rotating blade.
- the above process comprises the additional step of drying in a vacuum oven.
- the present invention also relates to an implant which comprises a porous collagen matrix surrounding and impregnating particles or granules of porous biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material comprising a sintered CAP core and at least one uniform and closed epitactically grown layer of nanocrystalline HAP deposited on top of the sintered CAP core, whereby the epitactically grown nanocrystals have the same size and morphology as human bone mineral, i.e. a length of 30 to 46 nm and a width of 14 to 22 nm.
- CAP/HAP porous biphasic calcium phosphate/hydroxyapatite
- the present invention also concerns the use of the above defined CAP/HAP bone substitute material, generally in the form of a particulate or a shaped body as an implant or prosthesis for supporting bone formation, bone regeneration, bone repair and/or bone replacement at a defect site in a human or animal.
- the present invention also relates to a method of promoting bone formation, bone regeneration and/or bone repair at a defect site in a human or animal by implanting the above defined CAP/HAP bone substitute material, generally in the form of a particulate or a shaped body.
- phase purity was performed using powder X-ray diffraction analysis.
- the bulk product from example 1 was crushed by using a jaw crusher (slot size 4 mm).
- the course granules were sieved by using a sieving machine and sieve inserts with mesh aperture 2 mm and 0.25 mm. After sieving the granule fractions were rinsed 2 times by using purified water for separating fine powder residuals adsorbed to the granules.
- the porous granules were dried for 10 hours at 120°C in a cabinet dryer.
- the control of particle size distribution was done by using laser diffraction technology.
- the cleanness of the particle surfaces after rinsing was controlled by surface observation using scanning electron microscopy.
- the work piece was placed and fixed into a 4-axis CNC milling machine equipped with a round-head hard metal milling cutter tool with a diameter of 3 mm.
- the cylinders were milled by using a helical milling route with a radius of 3 mm and a slope of 0.25 mm.
- the main speed of the work piece during the CNC milling process was 1700 rotations per minute, the maximum rotation speed of the helical milling route was calculated by an integral process within the CNC equipment and averages 10 rotations per minute.
- the cylindrical preforms were rinsed 2 times by using purified water for separating fine powder residuals adsorbed to the cylinder surface.
- the porous cylinders were dried for 10 hours at 120°C in a cabinet dryer.
- the cleanness of the preform surface after rinsing was controlled by surface observation using scanning electron microscopy.
- the correctness of the preform dimensions was controlled by using a slide gauge.
- Example 4 Preparation of an epitactically grown nanocrystalline HAP coating on the granules of sintered -TCP from Example 2
- transformation process was prepared by using 1.82 mol/1 sodium, 4.68 mol/1 hydrogen, 0.96 mol/1 phosphorus, 5.64 mol/1 oxygen, 0.01 mol/1 calcium and 0.71 mol/1 chlorine.
- the solution will be adjusted to a pH of 7.4 at a temperature of 40°C.
- the granules produced according to example 1 and 2 were immersed into the prepared solution and stored within a well tempered water bath (40°C) for a time calculated according a layer thickness at an average of 250 nm (10 hours) which equates to a phase composition of (w/w) 75 % alpha-TCP and 25% hydroxyapatite. After immersing the granules were rinsed 3 times by purified water to remove residuals from the buffered solution.
- the porous granules were dried for 4 hours at 120°C in a cabinet dryer.
- the phase composition of the granules were analyzed by Rietveld analysis of powder X-ray diffraction data, the crystal sizes of crystalline phases obtained by the coating process were analyzed by size-strain refinement of X- ray diffraction data according to the Bragg technique.
- the porosity of the granules was controlled by using mercury intrusion porosimetry, the surface morphology after coating was controlled by using scanning electron microscopy.
- Example 5 Preparation of an epitactically grown nanocrystalline HAP coating on the cylinders of sintered -TCP from Example 3
- the layer thickness was controlled using reflection high-energy electron diffraction (RHEED) and/or photoelectron spectroscopy (XPS).
- RHEED reflection high-energy electron diffraction
- XPS photoelectron spectroscopy
- Tables 2 and 3 show experimental data for an example showing the influence of the immersing time on the layer thickness and the phase composition, respectively, for porous a-TCP particles with nearly spherical geometry and size from 10 to 20 ⁇ , a porosity 25-40 vol.-%, a specific (inner) surface area of 50-60 m 2 /g/ a bulk density of 0.6-0.8 g/ml.
- Liquid Phase PBS buffered saline liquid, 20x, temperature 40°C.
- Example 7 Preparation of a slurry of collagen fibres derived from pig skin.
- Porcine hides were ground in a meat grinder to pieces of 1 to 20 mm.
- the water was removed using a water soluble solvent such as an alcohol or a ketone.
- the collagen fibres were defatted using a chlorinated hydrocarbon such as dichloroethane or methylene chloride or a non-chlorinated hydrocarbon such as hexane or toluene.
- a chlorinated hydrocarbon such as dichloroethane or methylene chloride or a non-chlorinated hydrocarbon such as hexane or toluene.
- the collagen was treated with a strong inorganic base at a pH above 12 for a period of 6 to 24 hours and treated with a strong inorganic acid at a pH of 0 to 1 for a period of 1 to 12 hours.
- the excess acid was removed by rinsing with water and the suspension was homogenized to a 0.5 to 2 % homogenous suspension of collagen fibres in the presence of a swelling regulator such as an inorganic salt.
- the suspension was dried by freeze-drying and the dry collagen fibres were successively cleaned with different organic solvents such as alcohols, ethers, ketones and chlorinated hydrocarbons, the solvents being then evaporated under vacuum to a solvent residue of less than 1 %.
- a slurry of collagen fibres was prepared by mixing the cleaned dry fibres obtained above with water.
- Example 8 Preparation of a plate of porous (CAP/HAP) bone substitute material impregnated with collagen fibers 594.2 g of the slurry of collagen fibers (corresponding to about 14.855 g of dry collagen) prepared in Example 7 and 119.7 g of porous granules of (CAP/HAP) bone substitute material prepared as described in Example 5 and having a particle size between 0.5 and 1.0 mm were thoroughly mixed during 30 minutes and the mixture was poured into a suction filter and dried by suction. The plate of (CAP/HAP) bone substitute material impregnated with collagen fibers was carefully removed from the suction filter and dried in a vacuum oven at about 35 °C for 48 hours. Pieces of that plate were cut for in vivo testing.
- CAP/HAP porous
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2822682A CA2822682C (en) | 2010-12-22 | 2011-12-21 | Bone substitute material |
DK11817517.3T DK2654816T3 (en) | 2010-12-22 | 2011-12-21 | BONE SUBSTITUTE MATERIAL |
AU2011348430A AU2011348430B2 (en) | 2010-12-22 | 2011-12-21 | Bone substitute material |
EP20110817517 EP2654816B1 (en) | 2010-12-22 | 2011-12-21 | Bone substitute material |
KR1020137017421A KR101599245B1 (en) | 2010-12-22 | 2011-12-21 | Bone substitute material |
US13/997,419 US9066995B2 (en) | 2010-12-22 | 2011-12-21 | Bone substitute material |
RU2013133731/15A RU2591087C2 (en) | 2010-12-22 | 2011-12-21 | Bone filler material |
PL11817517T PL2654816T3 (en) | 2010-12-22 | 2011-12-21 | Bone substitute material |
ES11817517.3T ES2532456T3 (en) | 2010-12-22 | 2011-12-21 | Bone substitute material |
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EP10015924 | 2010-12-22 | ||
EPEP10015924 | 2010-12-22 |
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WO2012084214A1 true WO2012084214A1 (en) | 2012-06-28 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/EP2011/006457 WO2012084214A1 (en) | 2010-12-22 | 2011-12-21 | Bone substitute material |
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US (1) | US9066995B2 (en) |
EP (1) | EP2654816B1 (en) |
KR (1) | KR101599245B1 (en) |
AU (1) | AU2011348430B2 (en) |
CA (1) | CA2822682C (en) |
DK (1) | DK2654816T3 (en) |
ES (1) | ES2532456T3 (en) |
PL (1) | PL2654816T3 (en) |
PT (1) | PT2654816E (en) |
RU (1) | RU2591087C2 (en) |
WO (1) | WO2012084214A1 (en) |
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WO2018041668A1 (en) * | 2016-09-01 | 2018-03-08 | Karl Leibinger Medizintechnik Gmbh & Co. Kg | Fiber-reinforced bioresorbable implant and method for producing same |
US10064892B2 (en) | 2013-07-18 | 2018-09-04 | Kuros Biosciences B.V. | Method for producing an osteoinductive calcium phosphate and products thus obtained |
WO2020249716A1 (en) * | 2019-06-14 | 2020-12-17 | Geistlich Pharma Ag | Collagen matrix or granulate blend of bone substitute material |
WO2020249714A1 (en) * | 2019-06-14 | 2020-12-17 | Geistlich Pharma Ag | Collagen matrix or granulate blend of bone substitute material |
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US10118827B2 (en) | 2013-05-10 | 2018-11-06 | Reed A. Ayers | Combustion synthesis of calcium phosphate constructs and powders doped with atoms, molecules, ions, or compounds |
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US9895354B2 (en) | 2014-04-04 | 2018-02-20 | University Of Kentucky Research Foundation | Bilayered calcium sulfate/calcium phosphate space-making composites with multiple drug delivery capabilities |
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US20130345825A1 (en) | 2013-12-26 |
PL2654816T3 (en) | 2015-05-29 |
KR101599245B1 (en) | 2016-03-03 |
RU2591087C2 (en) | 2016-07-10 |
EP2654816A1 (en) | 2013-10-30 |
RU2013133731A (en) | 2015-01-27 |
ES2532456T3 (en) | 2015-03-27 |
AU2011348430A1 (en) | 2013-07-04 |
PT2654816E (en) | 2015-03-11 |
EP2654816B1 (en) | 2015-02-11 |
DK2654816T3 (en) | 2015-03-23 |
US9066995B2 (en) | 2015-06-30 |
KR20140009282A (en) | 2014-01-22 |
CA2822682C (en) | 2018-10-30 |
CA2822682A1 (en) | 2012-06-28 |
AU2011348430B2 (en) | 2015-07-09 |
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